The overall goal of this program project is to identify and characterize new and alternative mechanistic targets by which estrogens and progestins are neuroprotective. This program of research is driven by a critical need to improve our understanding of steroid hormone neurobiology, a need that became evident following the results of the Women's Health Initiative Memory Study that identified effects of estrogen and/or progestins that were contrary to expectation. To address this need, we have organized a program of research consisting of 4 highly interactive research projects and 2 supportive cores. The studies proposed in these projects challenge the field to consider a novel membrane PR (Project 1), a mitochondria-localized estrogen receptor (Project 2), intracellular Ca2+channels, including IPS receptors and a novel mitochondrial ryanodine receptor (Project 3), and a previously ignored, naturally occurring estrogen, 17a-E2 (Project 4), as critical players in neuroprotection and/or neurogenesis. Supporting these projects will be the Administrative Core (Core A) that not only oversees the program of research, but will also provide biostatistical support and a common animal model (ovariectomized animals that have undergone transient cerebral ischemia) to the projects, the latter serving as a point of integration for the research performed in the individual projects. In addition, the Mass Spectrometry Core (Core B) will serve all 4 projects by providing powerful tools to assess brain steroid levels and for the routine identification and/or quantification of proteins and their posttranslational modifications, which will serve to enhance the Program's ability to define relevant mechanistic targets of estrogens and progestins. Through the successful completion of the proposed research, we expect to have identified key players in the neuroprotection cascade relevant to the protective effects of estrogen and progesterone. In particular, we will have identified the most protective hormone along with their important intracellular targets that are critical for protecting neural tissue, which can in turn, be exploited for the development of safer and more effective therapeutic strategies for treating the menopause and age associated disorders such as Alzheimer's disease, whose incidence and risk increases in the postmenopausal period. PRINCIPAL INVESTIGATOR: The Principal Investigator, Dr. Meharvan Singh, is a highly talented investigator. He completed his Ph.D. degree in Neuropharmacology from the University of Florida, Gainesville in 1994 followed by a three year postdoctoral fellowship at Columbia University. He has been on the faculty of the University of North Texas (UNT) since 2001, where he currently holds an associate professorship. Dr. Singh is qualified to serve as the director of this program and lead the proposed study for which he has been the driving force. REVIEW OF THE COMPONENTS CORE A: ADMINSTRATIVE CORE;DR. MEHARVAN SINGH DESCRIPTION (provided by applicant): The Administrative Core will manage the progress of the Program Project, which has the immediate goal of discovering novel mechanistic targets of steroid hormones in the brain. The Administrative Core has 4 Specific Aims: Aim 1: The Core will hold overall responsibility for the administration of the Program Project and will employ a talented administrative assistant to manage the day-to-day activities of the Program Project. In addition, 3 committees have been established to provide advice to the Director. Aim 2 is to manage the fiscal aspects of the Program Project. This will include setting up Project and Core accounts, reconciling accounts, providing budget reports to the investigators, ordering reagents and supplies when needed, tracking orders, reporting expenditures to the Health Science Center as well as NIA personnel. Aim 3 is to manage the high level of interactions between Projects and Cores. This will include facilitating/coordinating the exchange of scientific ideas (through regular meetings) as well as the sharing of resources, when needed. Further, there will be three major subcomponents of the Administrative Core that will support and manage the interactions between projects. The first will provide statistical support to all projects, including providing assistance with post hoc analyses of the data generated, and exploring correlations between the data sets generated by the individual projects. The second will be to procure, maintain and distribute animals to the projects and serve as a centralized resource for generation of the common animal model within this program of research (the ovariectomized mouse that has undergone transient cerebral ischemia). The third will provide database support by maintaining a web-based database that catalogues the resources available through the Program Project, and also provides a secure site for sharing of data among investigators. Aim 4 is to foster an environment for the intellectual interactions among program investigators, and between program investigators and the UNT Health Science Center community. Numerous mechanisms are in place or in development to foster such an environment, including the continued development of facilities, faculty and activities within the Institute for Aging and Alzheimer's Disease Research and the Center for Women's Health on campus.